Protein synthesis inhibitor explained

A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.^[1] While a broad interpretation of this definition could be used to describe nearly any compound depending on concentration, in practice, it usually refers to compounds that act at the molecular level on translational machinery (either the ribosome itself or the translation factor),^[2] taking advantages of the major differences between prokaryotic and eukaryotic ribosome structures.

Mechanism

In general, protein synthesis inhibitors work at different stages of bacterial mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer, and bacterial translocation) and termination:

Earlier stages

• Rifamycin inhibits bacterial DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit.
• alpha-Amanitin is a powerful inhibitor of eukaryotic DNA transcription machinery.

Initiation

• Linezolid acts at the initiation stage,^[3] probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.^[4]

Ribosome assembly

• Aminoglycosides prevent ribosome assembly by binding to the bacterial 30S ribosomal subunit.^[5]

Aminoacyl tRNA entry

• Tetracyclines and Tigecycline^[6] (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs.

Proofreading

• Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination.^[7]

Peptidyl transfer

• Chloramphenicol blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria.
• Macrolides (as well as inhibiting ribosomal translocation^[8] and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer.
• Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin, as well as inhibiting peptidyl transfer.^[9] Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide,^[9] as well as causing incomplete chains to be released.^[9]
• Geneticin, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes.^[10]
• Trichothecene mycotoxins are potent and non selective inhibitors of peptide elongation.^[11]

Ribosomal translocation

• Macrolides,^[8] clindamycin^[12] and aminoglycosides^[7] (with all these three having other potential mechanisms of action as well), have evidence of inhibition of ribosomal translocation.
• Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome.
• Ricin inhibits elongation by enzymatically modifying an rRNA of the eukaryotic 60S ribosomal subunit.^{[13] [14]}

Termination

• Macrolides^{[15] [16]} and clindamycin^{[15] [16]} (both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome.
• Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Thus, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis.
• Streptogramins also cause premature release of the peptide chain.

Protein synthesis inhibitors of unspecified mechanism

• Retapamulin^[17]
• Mupirocin
• Fusidic acid

Binding site

The following antibiotics bind to the 30S subunit of the ribosome:

• Aminoglycosides ^[18]
• Tetracyclines^[18]

The following antibiotics bind to the 50S ribosomal subunit:

• Chloramphenicol^[18]
• Clindamycin^[18]
• Linezolid^[18] (an oxazolidinone)
• Macrolides^[18]
• Telithromycin^[18]
• Streptogramins^[18]
• Retapamulin^[17]

See also

• Protein biosynthesis
• Bacterial translation
• Eukaryotic translation
• Archaeal translation

Notes and References

1. Web site: Protein Synthesis Inhibitors. Frank Lowy. Columbia University. 2021-01-27.
2. Web site: 7.344 Antibiotics, Toxins, and Protein Engineering, Spring 2007 . MIT OpenCourseWare .
3. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL . The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria . Antimicrob. Agents Chemother. . 42 . 12 . 3251–3255 . December 1998 . 9835522 . 106030 . 10.1128/AAC.42.12.3251.
4. Skripkin E, McConnell TS, DeVito J, etal . Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance . Antimicrobial Agents and Chemotherapy . 52 . 10 . 3550–3557 . October 2008 . 18663023 . 2565890 . 10.1128/AAC.01193-07.
5. Mehta. Roopal. Champney. W. Scott. 2003. Neomycin and Paromomycin Inhibit 30S Ribosomal Subunit Assembly in Staphylococcus aureus. Current Microbiology. 47. 3. 237–43. 10.1007/s00284-002-3945-9. 14570276. 23170091 .
6. Slover CM, Rodvold KA, Danziger LH . Tigecycline: a novel broad-spectrum antimicrobial. Ann Pharmacother. 41. 6. 965–972. June 2007. 10.1345/aph.1H543. 2009-12-19. 17519296. 5686856.
7. Web site: Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents . Pharmamotion . Flavio Guzmán . 2008-08-12 . dead . https://web.archive.org/web/20100312134115/http://pharmamotion.com.ar/protein-synthesis-inhibitors-aminoglycosides-mechanism-of-action-animation-classification-of-agents/ . 2010-03-12 .
8. https://web.archive.org/web/20081226204524/http://pharmamotion.com.ar/protein-synthesis-inhibitors-macrolides-mechanism-of-action-animation-classification-of-agents/ Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents
9. https://books.google.com/books?id=ekyv3I9ccIQC Page 212
10. Web site: Geneticin. Thermo Fisher Scientific.
11. Shifrin. Victor I.. Anderson. Paul. Trichothecene Mycotoxins Trigger a Ribotoxic Stress Response That Activates c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase and Induces Apoptosis. Journal of Biological Chemistry. 274. 20. 1999. 13985–13992. 0021-9258. 10.1074/jbc.274.20.13985. 10318810 . free.
12. http://sitemaker.umich.edu/mc3/clindamycin Wisteria Lane cases → CLINDAMYCIN
13. October 1988. Ricin binding and protein synthesis inhibition in human hematopoietic cell lines. Blood. 72. 4. 1357–1363. 10.1182/blood.V72.4.1357.1357. 3167211. Leonard JE, Grothaus CD, Taetle R. free.
14. June 1988. Ricin and alpha-sarcin alter the conformation of 60S ribosomal subunits at neighboring but different sites. Eur. J. Biochem.. 174. 3. 459–463. 10.1111/j.1432-1033.1988.tb14120.x. 3391162. Terao K, Uchiumi T, Endo Y, Ogata K. free.
15. Menninger JR. Mechanism of inhibition of protein synthesis by macrolide and lincosamide antibiotics. J Basic Clin Physiol Pharmacol. 6. 3–4. 229–250. 1995. 8852269. 10.1515/JBCPP.1995.6.3-4.229. 36166592.
16. Tenson T, Lovmar M, Ehrenberg M . The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J. Mol. Biol.. 330. 5. 1005–1014. July 2003. 10.1016/S0022-2836(03)00662-4. 12860123.
17. http://www.drugbank.ca/drugs/DB01256 Drugbank.ca > Showing drug card for Retapamulin (DB01256)
18. Book: Levinson . Warren . Review of medical microbiology and immunology . 2008 . McGraw-Hill Medical . New York . 978-0-07-149620-9 .